Distinct S-adenosylmethionine synthases link phosphatidylcholine to mitochondrial function and stress survival

S-adenosylmethionine (SAM), produced by SAM synthases, is critical for various cellular regulatory pathways and the synthesis of diverse metabolites. Humans and many other organisms express multiple SAM synthases. However, loss of different synthase activity can have distinct phenotypic effects. For instance, in Caenorhabditis elegans loss of sams-1 leads to enhanced heat shock survival and increased life span, but loss of sams-4 reduces heat stress survival. This provides a biological context to test the hypothesis that the enzymatic source of SAM impacts its function and to identify mechanistic connections. Here, we show that SAMS-1 contributes SAM to a variety of intermediary metabolic pathways, whereas SAMS-4 has a more limited role to support SAM-dependent protein transmethylation reactions. Mitochondria seem to be particularly impacted specifically by loss of sams-1; many mitochondrial metabolites are perturbed and there is an age-dependent decline of nuclear-encoded mitochondrial gene expression in these animals. We further demonstrate that reduced production of phosphatidylcholine in sams-1-deficient animals leads to mitochondrial fragmentation and subsequent loss of mitochondrial components. We propose that alterations in mitochondria are mechanistically linked to the increased survival in heat stress specific to sams-1-deficient animals.

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Publication Details

Journal
PLoS Biology
Published
2025-12-01
DOI
https://doi.org/10.1371/journal.pbio.3003075
Primary Topic
Folate and B Vitamins Research
Type
article
Field-Weighted Citation Impact
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article

Distinct S-adenosylmethionine synthases link phosphatidylcholine to mitochondrial function and stress survival

Matthew J. Fanelli, Daniel Promislow, Amy K. Walker, T. Ngyuen et al.
PLoS Biology
Folate and B Vitamins Research
article

Distinct S-adenosylmethionine synthases link phosphatidylcholine to mitochondrial function and stress survival

Matthew J. Fanelli, Daniel Promislow, Amy K. Walker, T. Ngyuen, Alexander Munden, Rachel Walker, Lisa C. Crowley, Adwait Anand Godbole, Caroline A. Lewis, Daniel Raftery, Dana L. Miller, Dominique S. Lui, Maria Ericsson, Katherine M. Edwards, Kasturi Biswas, Jessica B. Spinelli, Benjamin R. Harrison, Daniel P Higgins, Arjamand Mushtaq, Danijel Djukovic, John D. Haley
article en

Abstract

S-adenosylmethionine (SAM), produced by SAM synthases, is critical for various cellular regulatory pathways and the synthesis of diverse metabolites. Humans and many other organisms express multiple SAM synthases. However, loss of different synthase activity can have distinct phenotypic effects. For instance, in Caenorhabditis elegans loss of sams-1 leads to enhanced heat shock survival and increased life span, but loss of sams-4 reduces heat stress survival. This provides a biological context to test the hypothesis that the enzymatic source of SAM impacts its function and to identify mechanistic connections. Here, we show that SAMS-1 contributes SAM to a variety of intermediary metabolic pathways, whereas SAMS-4 has a more limited role to support SAM-dependent protein transmethylation reactions. Mitochondria seem to be particularly impacted specifically by loss of sams-1; many mitochondrial metabolites are perturbed and there is an age-dependent decline of nuclear-encoded mitochondrial gene expression in these animals. We further demonstrate that reduced production of phosphatidylcholine in sams-1-deficient animals leads to mitochondrial fragmentation and subsequent loss of mitochondrial components. We propose that alterations in mitochondria are mechanistically linked to the increased survival in heat stress specific to sams-1-deficient animals.

PLoS BiologyVol. 23(12)
Harvard University (US), University of Massachusetts Chan Medical School (US), University of Washington (US)
Openalex Percentile: Top 46%
Folate and B Vitamins Research
DOIOpen Access PDFOpenAlex
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